The specific aims of ClinSeq include: 1. Pilot the development of a robust infrastructure for the generation and use of LSMS data from subjects in a clinical research setting. This will involve the coupling of the NISC production-oriented DNA sequencing group with the NIH Clinical Research Center. We will establish technical expertise for generating, handling, and interpreting LSMS clinical research data. 2. Use LSMS data to address biomedical research questions. For example: (l) testing associations of genomic variants with quantitative traits identified in subjects (such as atherosclerosis and lipid levels); (2) using LSMS data to identify subsets of subjects from the prospective cohort, who can then be invited to return to the NIH Clinical Research Center for additional phenotyping and in-depth study: and (3) using this cohort for replication studies of associations of genomic variants and phenotypes. A cohort of 1,000 individuals will be evaluated at the NIH Clinical Research Center for a set of cardiovascular phenotypic features, including, but not limited to, coronary artery calcification, lipid profiles, and blood pressure. Participants will be selected to fall within a spectrum of coronary artery calcification from normal to disease phenotype. Participants undergo a clinical evaluation, targeted clinical tests, and blood sample collection for genomic analysis and they will provide baseline information about pertinent health behavior and a family history. Exome sequencing of peripheral blood DNA will be performed on all samples and has been completed in >800 subjects to date. Importantly, ClinSeq subjects will be consented for return of results (both research and clinical results) and for re-contact for iterative phenotyping. ClinSeq was designed in a way that will provide the long-term potential for pursuing many different clinical projects. We propose to select subsets of subjects from the ClinSeq dataset, identified by their genomic attributes, explore their phenotypic manifestations, as a new path to understanding genotype-phenotype relationships. In the most recent reporting period we have successfully interpreted exomes of 600 participants for serious, disease-causing variants in a number of disease categories including cancer susceptibility, cardiomyopathy, cardiac dysrhythmias, malignant hyperthermia, and peripheral neurologic disorders. We are currently annotating subjects for an addition set of rare dominant disorders and recessive carrier status.